Preclinical development of ARRY-142886, a potent and selective MEK inhibitor

Abstract

3890 MEK is a critical kinase in the signal transduction pathway for many growth factor receptors, including EGF-R, IGF-1R and PDGF-R, which provide growth signals to cancer cells. It is downstream of Ras and Raf proteins that are often mutated and abnormally active in cancer. The MEK inhibitor, ARRY-142886, inhibits the proliferation of several human cancer cell lines in culture, including HT29, Malme-3M, SK-MEL-28, MIA PaCa2, and SK-MEL-2. We have confirmed in vivo efficacy of ARRY-142886 in several tumor xenograft models in mice. In an HT29 human colon carcinoma model, dose-dependent inhibition of tumor growth was observed. Doses of 10 mg/kg, BID, PO resulted in greater than 50% tumor growth inhibition. Of note, in the BxPC3 human pancreatic carcinoma model, tumor regression was seen at doses of 10, 25 or 50 mg/kg, BID, PO. In these studies, tumors were excised and analyzed for ERK phosphorylation. Consistent with ARRY-142886’s mechanism of action, tumor growth inhibition correlated with decreased phospho-ERK levels in tumors. The effects of ARRY-142886 on tumor re-growth were also evaluated in a BxPC3 model. After three weeks of dosing (25 or 50 mg/kg, BID, PO), treatment was stopped for one week, during which time tumor growth resumed. Mice were then treated for an additional 3 weeks at the same doses. ARRY-142886 was effective in reducing tumor size and maintaining tumor growth inhibition of the re-established tumors, demonstrating that the tumors were still sensitive to ARRY-142886 after a dosing holiday. ARRY-142886 has shown efficacy in other xenograft models including MIA PaCa2, A549, Colon26, PANC-1, LoVo, Calu6, HCT116, MDA-MB-231, ZR-75-1 and LOX. These studies confirm that ARRY-142886 can block ERK phosphorylation in tumors and has broad anti-tumor effects in vivo.